Process for the Preparation of Cycloheptapyridine CGRP Receptor Antagonists

ABSTRACT

The disclosure generally relates to a process for the preparation of compounds of formula I, including synthetic intermediates which are useful in the process.

CROSS REFERENCE TO RELATED APPLICATIONS

This Divisional application claims the benefit of U.S. Ser. No.13/236,072 filed Sep. 19, 2011, now allowed, which in turn is a U.S.Non-Provisional application which claims the benefit of U.S. Provisionalapplication Ser. No 61/392,183 filed Oct. 12, 2010, now expired.

BACKGROUND OF THE INVENTION

The disclosure generally relates to a synthetic process for preparingcompounds of formula I including the preparation of chemicalintermediates useful in this process.

CGRP inhibitors are postulated to be useful in pathophysiologicconditions where excessive CGRP receptor activation has occurred. Someof these include neurogenic vasodilation, neurogenic inflammation,migraine, cluster headache and other headaches, thermal injury,circulatory shock, menopausal flushing, and asthma. CGRP antagonistshave shown efficacy in human clinical trials. See Davis C D, Xu C. CurrTop Med Chem. 2008 8(16):1468-79; Benemei S, Nicoletti P, Capone J G,Geppetti P. Curr Opin Pharmacol. 2009 9(1):9-14. Epub 2009 Jan. 20; Ho TW, Ferrari M D, Dodick D W, Galet V, Kost J, Fan X, Leibensperger H,Froman S, Assaid C, Lines C, Koppen H, Winner P K. Lancet. 2008372:2115. Epub 2008 Nov. 25; Ho T W, Mannix L K, Fan X, Assaid C, FurtekC, Jones C J, Lines C R, Rapoport A M; Neurology 2008 70:1304. Epub 2007Oct. 3.

CGRP receptor antagonists have been disclosed in PCT publications WO2004/092166, WO 2004/092168, and WO 2007/120590. The compound(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-1)]pyridin-1-yl)piperidine-1-carboxylate is an inhibitor of thecalcitonin gene-related peptide (CGRP) receptor.

For purposes of large-scale production there is a need for ahigh-yielding synthesis of compound of formula I and related analogsthat is both efficient and cost-effective.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a process for the preparation of acompound of formula I, or a salt thereof, where Ar¹ is phenylsubstituted with 0-3 substituents selected from the group consisting ofcyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO₂

comprising the reductive amination and alcohol deprotection of acompound of formula IV where R¹ is selected from the group consisting oftrialkylsilyl, alkoxy, alkylcarbonyl, benzyl, substituted benzyl,benzoyl, and pivaloyl to a compound of formula II where R¹ is hydrogen,and coupling the compound of formula II, or a salt thereof, with acompound of formula III where R² is selected from the group consistingof imidazolyl, pyrrolyl, N-hydroxysuccinimidyl, chloro, phenoxy,substituted phenoxy, phenylthio, and substituted phenylthio.

Another aspect of the invention is a process for the preparation of acompound of formula I, or a salt thereof, where Ar¹ is phenylsubstituted with 0-3 substituents selected from the group consisting ofcyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO₂

comprising coupling a compound of formula II, or a salt thereof, whereR¹ is hydrogen, or a salt thereof, with a compound of formula III, or asalt thereof, where R² selected from the group consisting of imidazolyl,pyrrolyl, N-hydroxysuccinimidyl, chloro, phenoxy, substituted phenoxy,phenylthio, and substituted phenylthio.

Another aspect of the invention is where the compound of formula II is

or a salt thereof, and the compound of formula III is

or a salt thereof.

Another aspect of the invention is a process for the preparation of acompound of formula II, or a salt thereof, where Ar¹ is phenylsubstituted with 0-3 substituents selected from the group consisting ofcyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkylSO₂ and R¹is hydrogen,

comprising the reductive amination and deprotection of a compound offormula IV, or a salt thereof, where Ar¹ is phenyl substituted with 0-3substituents selected from the group consisting of cyano, halo, alkyl,haloalkyl, alkoxy, haloalkoxy, and alkylSO₂ and R¹ is trialkylsilyl,alkoxy, alkylcarbonyl, benzyl, substituted benzyl, benzoyl, andpivaloyl.

Another aspect of the invention is a process where Ar¹ is2,3-difluorophenyl and where R¹ is triisopropylsilyl for the compound offormula IV.

Another aspect of the invention is a process for the preparation of acompound of formula III, or a salt thereof, where R² is imidazolyl

comprising coupling 3-N-piperidin-4-ylpyridine-2,3-diamine, or a saltthereof, or 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one, or asalt thereof, with carbonyl diimidazole or triphosgene and imidazole.

Another aspect of the invention is a compound of formula II, or a saltthereof, where Ar¹ is phenyl substituted with 0-3 substituents selectedfrom the group consisting of cyano, halo, alkyl, haloalkyl, alkoxy,haloalkoxy, and alkylSO₂ and R¹ is hydrogen or trialkylsilyl, alkoxy,alkylcarbonyl, benzyl, substituted benzyl, benzoyl, and pivaloyl.Another aspect of the invention is a compound of formula II where Ar¹ is2,3-difluorophenyl and R¹ is hydrogen or a salt thereof. Another aspectof the invention is a compound of formula II which is thedihydrochloride salt.

Another aspect of the invention is a compound of or formula II where Ar¹is 2,3-difluorophenyl and R¹ is triisopropylsilyl or a salt thereof.Another aspect of the invention is a compound of formula II which is thedihydrochloride salt.

Another aspect of the invention is a compound of formula III, or a saltthereof, where R² is selected from the group consisting of imidazolyl,pyrrolyl, N-hydroxysuccinimidyl, chloro, phenoxy, substituted phenoxy,phenylthio, and substituted phenylthio. Another aspect of the inventionis a compound of claim 12 where R² is imidazolyl.

Unless specified otherwise, these terms have the following meanings“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons, preferably 1 to 3 carbons. “Alkenyl” means a straight orbranched alkyl group composed of 2 to 6 carbons with at least one doublebond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7carbons. “Hydroxyalkyl,” “alkoxy” and other terms with a substitutedalkyl moiety include straight and branched isomers composed of 1 to 6carbon atoms for the alkyl moiety. “Haloalkyl” and “haloalkoxy” includeall halogenated isomers from monohalo substituted alkyl to perhalosubstituted alkyl. “Aryl” includes carbocyclic and heterocyclic aromaticring systems.

Those skilled in the art understand that there are a variety ofalternative reagents and solvents that can be interchanged. Thefollowing definitions are meant to serve as non-limiting examples toillustrate a term and are not meant to limit the definition to theexamples listed.

Some suitable protecting groups at R¹ include trialkylsilyl, alkylether, benzyl ether, alkyl carbonate, benzyl carbonate, and ester.Trialkylsilyl includes TMS, TES, TIPS, TPS, TBDMS, and TBDPS. Alkylethers include methyl, MOM, BOM, PMBM, t-Butoxymethyl, SEM, THP, t-Bu,and allyl. Benzyl ether includes methoxybenzyl, dimethoxybenzyl,trifluoromethylbenzyl, nitrobenzyl, dinitrobenzyl, cyanobenzyl, andhalobenzyl, diphenylmethyl and triphenylmethyl. Alkyl carbonate includesmethyl, ethyl, isobutyl, vinyl, allyl and nitrophenyl. Substitutedbenzyl carbonate includes methoxybenzyl, dimethoxybenzyl andnitrobenzyl. Ester includes pivolate, adamantoate, benzoate,phenylbenzoate, and mesitoate.

Some suitable leaving groups at R² include imidazolyl, pyrrolyl,N-hydroxysuccinimidyl, chloro, substituted phenoxy, and substitutedphenylthio. Substituted phenoxy includes nitrophenoxy, cyanophenoxy, andtrifluoromethylphenoxy. Substituted phenylthio includes nitrophenylthio,cyanophenylthio, and trifluoromethylphenylthio.

Some suitable reductive amination conditions include using ammonia,hydroxyamine, protected hydroxyamine (for example, methoxyamine,benzyloxyamine, acetoxyamine), benzylamine, and the salts of theseaminating reagents (for example, ammonium acetate, ammonium chloride).Benzyl includes methoxybenzyl, dimethoxybenzyl, trifluoromethylbenzyl,nitrobenzyl, dinitrobenzyl, cyanobenzyl, and halobenzyl, diphenylmethyland triphenylmethyl.

Some suitable reagents for dehydrating agents in the reductive aminationinclude titanium alkoxides, titanium chloride, mixed titaniumalkoxides/chlorides, aluminum chloride, zirconium chloride, tinchloride, boron trifluoride, copper sulfate, magnesium sulfate, andmolecular sieves. Titanium alkoxides include isopropoxide, propoxide,ethoxide, methoxide, butoxide, and t-butoxide.

Some suitable reduction conditions include transition metal catalyzedhydrogenations with for example, palladium, platinum, or iridiumcatalysts, metal hydrides of aluminum and boron, and zinc with aceticacid. Some catalysts include palladium on alumina, palladium on calciumcarbonate, palladium-lead on calcium carbonate, palladium on carbon andPerlman's catalyst.

Some suitable acids for deprotecting the alcohol include any acid orfluoride containing reagent. For example, hydrogen chloride, hydrogenbromide, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid,trifluoroacetic acid, hydrogen fluoride, hydrogen fluoride-pyridine, andtetrabutylammonium fluoride.

Some suitable bases for the coupling include group I and II metalalkoxides (for example, sodium methoxide, potassium t-butoxide andsodium t-butoxide), group I metal disilazides (for example potassiumdisilazide), group I and II hydrides (for example, sodium hydride),group I amides (for example, lithium diisopropylamide), and group Imetal alkydes (for example, butyl lithium).

Synthetic Methods

The following methods are for illustrative purposes and are not intendedto limit the scope of the invention. Those skilled in the art understandthat there will be a number of equivalent methods for the preparation ofthese compounds and that the synthesis is not limited to the methodsprovided in the following examples. For example, some reagents andsolvents may have equivalent alternatives known to those in the art. Thevariables describing general structural formulas and features in thesynthetic schemes are distinct from and should not be confused with thevariables in the claims or the rest of the specification. Thesevariables are meant only to illustrate how to make some of the compoundsof the invention.

Abbreviations used in the description generally follow conventions usedin the art. Some abbreviations are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd “for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry , “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tic” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “¹H” for proton, “δ” for delta,“s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m”for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”,“E”, and “Z” are stereochemical designations familiar to one skilled inthe art.

Scheme 1 illustrates a synthesis of formula I compounds.

DESCRIPTION OF SPECIFIC EMBODIMENTS Example 1

(6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine

To a 100 mL hastelloy autoclave reactor was charged(65,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one(5.00 g, 11.22 mmol), 1,4-dioxane (50 mL) and titaniumtetra(isopropoxide) (8.33 mL, 28.11 mmol). The reactor was purged threetimes with nitrogen and three times with ammonia. After the purge cyclewas completed, the reactor was pressurized with ammonia to 100 psig. Thereaction mixture was heated to 50° C. (jacket temperature) and stirredat a speed to ensure good mixing. The reaction mixture was aged at 100psig ammonia and 50° C. for 20 h. The mixture was then cooled to 20° C.then 5% Pd/Alumina (1.0 g, 20 wt %) was charged to the autoclavereactor. The reactor was purged three times with nitrogen and threetimes with hydrogen. After the purged cycle completed, the reactor waspressurized with hydrogen to 100 psig and mixture was heated to 50° C.(jacket temperature) and stirred at a speed to ensure good mixing. Thereaction mixture was aged at 100 psig H₂ and 50° C. for 23 h (reactorpressure jumped to ˜200 psig due to soluble ammonia in the mixture). Themixture was then cooled to 20° C. then filtered then transferred to a100 ml 3-necked flask. To the mixture water (0.55 mL) was added dropwise, which resulted in yellow slurry. The resulting slurry was stirredfor 30 min then filtered, then the titanium dioxide cake was washed with1,4-dioxane (30 mL). The filtrate was collected and the solvent wasremoved. The resulting oil was dissolved in isopropanol (40 mL). To thesolution ˜5N HCl in isopropanol (9.0 ml) was added drop wise resultingin a thick slurry. To the slurry isopropyl acetate (60 ml) was added andheated to 45° C. for 10 min and then cooled to 22° C. over approximately3 h to afford a white solid (3.0 g, 51.5%). ¹H NMR (500 MHz, CD₃OD) δppm 8.89 (d, J=5.3, 1H), 8.42 (bs, 1H), 8.05 (bs, 1H), 7.35 (dd, J=8.19,16.71), 7.2 (bs, 2H), 7.22 (m, 1H) 7.15 (m, 1H), 5.7 (dd, J =1.89,J=8.51), 5.4 (m, 1H), 3.5 (m, 1H), 1.9-2.5 (B, 4h) 1.4 (sept, J=15.13,3H), 1.2 (t, J=7.57 18H); ¹³C NMR (125 MHz, CD₃OD) δ 153.5, 151.6,151.5, 151.3, 149.4, 143.4, 135.03, 129.8, 129.8, 127.8, 126.8, 126.4,118.6, 72.4, 54.1, 41.4, 34.3, 32.3, 25.4, 18.6, 18.5, 13.7, 13.6, 13.5,13.3.

Example 2

(6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol

To a 250 ml flask was charged(65,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-aminedi HCl salt (15 g, 25.88 mmol) and a solution of isopropanol:water (45mL : 15 mL). The mixture was heated to 82° C. for 6 h then dried viaazeotropic distillation at atmospheric pressure using isopropanol untilthe KF was less than <3%. After fresh isopropanol (25 ml) was added, themixture was heated to 70° C. and then isopropyl acetate (45 ml) wasadded that resulting in a white slurry. The slurry cooled to 22° C. for15 min to afford a white solid (9.33 g, 99%). ¹H NMR (500 MHz CD₃OD) δ8.77 (d, J=5.7 Hz, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.11 (dd, J=6.0, 8.2 Hz,1H), 7.21-7.32 (m, 3H), 5.53 (dd, J=3.8, 9.8 Hz, 1H) 5.33 (d, J=9.8 Hz,1H), 3.5 (bm, 1H), 2.25-2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); ¹³CNMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6,141.8, 135.7, 130.6, 127.7, 126.8, 118.9, 70.0, 54.9, 42.2, 34.5, 33.4.

Example 3

(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate

To a round bottom flask was charged(5S,65,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-oldihydrochloride (1.00 g, 2.73 mmol) and dichloromethane (15 mL). Asolution of sodium carbonate (0.58 g, 5.47 mmol), 20 wt % aqueous sodiumchloride (5 mL), and water (10 mL) was added and the biphasic mixturewas aged for 30 min. The phases were allowed to separate and the organicstream was retained. The dichloromethane solvent was then switched withazeotropic drying to tetrahydrofuran, with a final volume of (15 mL). At20° C. was added,1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one(0.95 g, 3.01 mmol), followed by a 20 Wt % potassium tert-butoxidesolution in THF (4 mL, 6.20 mmol). The thin slurry was aged for 1 h, andthen the reaction was quenched with the addition of 20 wt % aqueoussodium chloride (5 mL) and 20 wt % aqueous citric acid (2.5 mL). Thelayers were allowed to separate and the organic rich layer was retained.The organic layer was washed with 20 wt % aqueous sodium chloride (15mL). The organic tetrahydrofuran stream was then concentrated in vacuoto afford an oil which was resuspended in dichloromethane (20 mL) anddried with MgSO₄. The dichloromethane stream was concentrated in vacuoto afford an oil, which was crystallized from ethanol:heptane to afforda white solid (1.14 g, 78.3%). LCMS: [M+H]=535: ¹H NMR (600 MHz,d₆-DMSO) δ 11.58 (1H, bs), 8.45 (1H, bd), 8.03 (1H, d, J=7.3 Hz), 7.91(1H, bs), 7.54 (1H, bd), 7.36 (1H, bm), 7.34 (1H, bm), 7.28 (1H, m),7.21 (1H, m), 7.01 (1H, bs), 6.01 (1H, dd, J=3.2, 9.8 Hz), 4.48 (1H, d,J=9.5 Hz), 4.43 (1H, bm), 4.38 (1H, bm), 4.11 (1H, bm), 3.08 (1H, bm),2.93 (1H, bm), 2.84 (1H, m), 2.62 (1H, bm), 2.20 (2H, bm), 2.13 (1H,bm), 2.12 (1H, bm), 1.75 (1H, bm), 1.72 (1H, bm), 1.66 (1H, bm); ¹³C NMR(125 MHz, d₆-DMSO) δ 156.6, 154.2, 153.0, 149.8, 148.1, 146.4, 143.5,139.6, 137.4, 134.0, 132.8, 124.7, 124.5, 123.3, 122.2, 116.3, 115.0,114.3, 73.7, 52.8, 50.0, 43.8, 43.3, 32.0, 30.3, 28.6; mp 255° C.

Example 4

1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

To a round bottom flask was added, 1,1′-carbonyldiimidazole (8.59 g,51.4 mmol), diisopropylethylamine (12.6 mL, 72.2 mmol) andtetrahydrofuran (100 mL). This mixture was warmed to 40° C. and aged for10 min, after which1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride(10 g, 34.3 mmol) was added. The slurry was aged at 40° C. for 3 h, andthen upon reaction completion, the solvent was swapped to acetonitrilewhich afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H]=313; ¹HNMR (400 MHz, d₆-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J=8.0Hz), 7.73 (1H, d, J=4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd,J=4.0, 8.0 Hz), 4.52, (1H, dd, J=8.0, 12.0 Hz), 4.05 (2H, bd, J=8.0 Hz),3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J=12.0 Hz); ¹³C NMR (100 MHz,d₆-DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 118.7,116.4, 115.2, 49.3, 45.1, 28.5; mp 226° C.

Example 5

1-(1-(1H-imidazole-1-carbonyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

To a 250 ml round bottom flask was added3-N-piperidin-4-ylpyridine-2,3-diamine dihydrochloride (10 g, 52 mmol)and acetonitrile (100 mL). Triethyl amine (11.44 g, 113 mmol) and1,1′-Carbonyldiimidazole (18.34 g, 113 mmol) were added at ambienttemperature and the mixture was stirred for 2 h. The solvent wasevaporated under vacuum to ˜30 ml reaction volume and isopropyl acetate(50 mL) was added into the resulting slurry at 40° C. The slurry wascooled to 10-15° C. and then stirred for 1 h to afford an off whitesolid (10 g, 85%).

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

We claim:
 1. A compound of formula II, or a salt thereof, where Ar¹ isphenyl substituted with 0-3 substituents selected from the groupconsisting of cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, andalkylSO₂ and R¹ is hydrogen or trialkylsilyl, alkoxy, alkylcarbonyl,benzyl, benzoyl, and pivaloyl.


2. The compound of claim 1 where Ar¹ is 2,3-difluorophenyl and R¹ ishydrogen or a salt thereof.
 3. The compound of claim 2 which is thedihydrochloride salt.
 4. The compound of claim 1 where Ar¹ is2,3-difluorophenyl and R¹ is triisopropylsilyl or a salt thereof.
 5. Thecompound of claim 4 which is the dihydrochloride salt.